Epinephrine spray formulations

ABSTRACT

The present invention is directed to epinephrine spray formulations. The present invention is further directed to methods of treating anaphylaxis by administering epinephrine spray formulations to subjects in need of such treatments.

FIELD OF THE INVENTION

The present invention is directed to epinephrine spray formulations. Thepresent invention is further directed to methods of treating anaphylaxisby administering epinephrine spray formulations to subjects in need ofsuch treatments.

BACKGROUND OF THE INVENTION

Epinephrine (i.e. adrenaline) is a catecholamine with the followingchemical structure:

Epinephrine stimulates the alpha- and beta- adrenergic receptors of thesympathetic nervous system. Epinephrine binds to these adrenergicreceptors leading to relief of many life-threatening symptoms ofanaphylaxis including: relaxation of the smooth muscle in the bronchi ofthe lungs opening up the constricted airways; constriction of the bloodvessels leading to decreased swelling of the tongue and throat andincreased blood pressure; and finally, increased heart rate preventingor reversing cardiovascular collapse.

Epinephrine is commercially available as an injection (Adrenalin® atrademark of and available from Par Sterile Products, LLC) and anauto-injector (EpiPen® a trademark of and available from Mylan, Inc. andAuviQ® a trademark of and available from Sanofi Corporation).Epinephrine was previously available as a nasal spray (Adrenalin®) andan aerosol spray (Primatene® Mist trademark of ArmstrongPharmaceuticals, Inc.). Racepinephrine is commercially available as a2.25% oral inhalation solution for use in nebulizers (S2® is availablefrom Nephron Pharmaceuticals, Inc.). Epinephrine differs fromracepinephrine in that epinephrine consists of only the L-isomer andracepinephrine is a 50/50 mixture of both the L- and D-isomers.

U.S. Pat. No. 8,628,805 is directed to a stable liquidadrenaline/bisulfite composition wherein the molar ratio of adrenalineto bisulfite is 1.31-2.20:1. U.S. Patent Application Publication No.2012/0322884 A1 is directed to epinephrine nanoparticles, which can beincorporated into sublingual tablets. U.S. Patent ApplicationPublication No. 2007/0202163 A1 is directed to epinephrine tablets forsublingual administration, which contain between 12% and 48%epinephrine. World Intellectual Property Organization (“W.I.P.O.”)Publication No. 2014/127018 A1 is directed to a stable aqueousepinephrine formulation that requires cyclodextrin. W.I.P.O. PublicationNo. 2014/057365 A1 is directed to an injectable epinephrine formulation.

While there are various epinephrine formulations currently available,there remains a need in the art for a quick-onset spray formulation.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to epinephrine sprayformulations comprising:

from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof,preferably the salt is selected from the group consisting of citrate,hydrochloride, halide, sulfate, phosphate, acetate, maleate, succinate,ascorbate, carbonate, mesylate and lactate;

from about 1% w/w to about 80% w/w water, preferably from about 5% toabout 77% w/w, more preferably from about 10% to about 65% w/w or fromabout 15% to about 80% w/w; optionally, from about 1% w/w to about 99%w/w of a solvent selected from the group consisting of ethanol,glycerin, propylene glycol, polyethylene glycol 400 and a combinationthereof; and

optionally, from about 0.1% w/w to about 60% w/w of at least one acid,

wherein the formulation has a pH from about 2 to about 5.5.

In one aspect, the present invention is directed to epinephrine sprayformulations comprising:

from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof,preferably the salt is selected from the group consisting of citrate,hydrochloride, halide, sulfate, phosphate, acetate, maleate, succinate,ascorbate, carbonate, mesylate and lactate;

from about 1% w/w to about 99% w/w of a solvent selected from the groupconsisting of water, ethanol, glycerin, propylene glycol, polyethyleneglycol 400 and a combination thereof, preferably the solvent is acombination of water, ethanol and propylene glycol or water;

from about 0.1% w/w to about 60% w/w of at least one acid, preferablythe at least one acid is diluted hydrochloric acid,

wherein the formulation has a pH from about 2 to about 5.5.

In another aspect, the present invention is directed to epinephrinespray formulations, wherein the formulation is free of a propellant.

In another aspect, the present invention is directed to epinephrinespray formulations, wherein the formulation does not contain sorbitol.

In another aspect, the solvent of the present invention comprises fromabout 1% w/w to about 30% w/w glycerin.

In another aspect, the epinephrine spray formulations of the presentinvention further comprise a permeation enhancer comprising caprylicacid, preferably the caprylic acid is at a concentration from about 0.1%w/w to about 10% w/w, more preferably from about 0.1% w/w to about 5w/w.

In another aspect, the permeation enhancer of the present inventionfurther comprises a second compound selected from the group consistingof menthol, limonene, carvone, methyl chitosan, polysorbates, sodiumlauryl sulfate, glyceryl oleate, caproic acid, enanthic acid, pelargonicacid, capric acid, undecylenic acid, lauric acid, myristic acid,palmitic acid, oleic acid, stearic acid, linolenic acid, arachidonicacid, benzethonium chloride, benzethonium bromide, benzalkonium chloride(BKC), cetylpyridium chloride, edetate disodium dihydrate (EDTA), sodiumdesoxycholate, sodium deoxyglycolate, sodium glycocholate, sodiumcaprate, sodium taurocholate, sodium hydroxybenzoyal amino caprylate,dodecyl dimethyl aminopropionate, L-lysine, glycerol oleate, glycerylmonostearate, citric acid, peppermint oil and a combination thereof,preferably menthol, preferably the menthol is at a concentration fromabout 0.1% to about 5% w/w, more preferably from about 0.1% to about 1%w/w.

In another aspect, the epinephrine spray formulations of the presentinvention contain no permeation enhancer.

In another aspect, the epinephrine spray formulations of the presentinvention further comprise an isotonicity agent comprising sodiumchloride.

In another aspect, the epinephrine spray formulations of the presentinvention further comprise a stabilizer selected from the groupconsisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene(BHT), ascorbic acid, methionine, sodium ascorbate, sodium thiosulfate,sodium bisulfite, sodium metabisulfite, ascorbyl palmitate,thioglycerol, alpha tocopherol (vitamin E), cysteine hydrochloride,benzalkonium chloride (“BKC”), citric acid, ethylenediaminetetraaceticacid (EDTA), sodium citrate, propyl gallate, 8-hydroxyquinoline, boricacid, histidine and combinations thereof, preferably the stabilizercomprises EDTA at a concentration from about 0.005% w/w to about 0.5%w/w, preferably the stabilizer comprises sodium bisulfite, sodiummetabisulfite or a combination thereof at a concentration from about0.005% w/w to about 5% w/w and preferably the stabilizer comprises BKCat a concentration from about 0.005% to about 0.5% w/w.

In another aspect, the epinephrine spray formulations of the presentinvention further comprise a preservative selected from the groupconsisting of butyl paraben, methyl paraben, ethyl paraben, propylparaben, sodium benzoate, chlorobutanol, benzalkonium chloride (BKC),benzoic acid and combinations thereof, preferably BKC at a concentrationfrom about 0.005% w/w to about 0.5% w/w.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

from about 0.1% to about 15% w/w epinephrine, or a salt thereof;

from about 1% to about 65% w/w hydrochloric acid with a normality fromabout 0.1 to 12N;

from about 2% to about 60% w/w ethanol;

from about 2% to about 98% w/w water;

from about 1% to about 20% w/w propylene glycol;

from about 0.001% to about 1% w/w sodium bisulfite;

from about 0.001% to about 1% w/w sodium metabisulfite;

from about 0.005% to about 1 w/w EDTA;

optionally, a permeation enhancer selected from the group consisting offrom about 0.5% to about 15% w/w caprylic acid, from about 0.1% to about10% w/w menthol and a combination thereof; and

optionally, benzalkonium chloride at a concentration from about 0.001%to about 0.1% w/w, wherein the formulation optionally has a pH fromabout 3 to about 5.5.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

from about 0.1% to about 15% w/w epinephrine, or a salt thereof;

from about 1% to about 65% w/w hydrochloric acid with a normality fromabout 0.1 to 12N;

from about 2% to about 98% w/w water;

from about 0.001% to about 7.5% w/w sodium bisulfite;

from about 0.001% to about 7.5% w/w sodium metabisulfite;

from about 0.005% to about 1 w/w EDTA;

from about 0.1% to about 1% sodium chloride;

optionally, benzalkonium chloride at a concentration from about 0.001%to about 0.1% w/w, wherein the formulation optionally has a pH fromabout 3 to about 5.5.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

from about 0.1% to about 15 w/w epinephrine, or a salt thereof;

from about 1% to about 65% w/w hydrochloric acid with a normality fromabout 0.1 to 12N;

from about 2% to about 98% w/w water, preferably from about 10% to about65% w/w;

from about 0.005% to about 1% w/w sodium bisulfite;

from about 0.005% to about 1 w/w EDTA;

from about 0.005% to about 0.5% w/w BKC;

optionally, from about 2% to about 60% w/w ethanol;

optionally, from about 1% to about 20% w/w propylene glycol;

optionally, from about 0.05% to about 5% w/w sodium chloride;

optionally, benzalkonium chloride at a concentration from about 0.001%to about 0.1% w/w,

wherein the formulation optionally has a pH from about 3 to about 5.5.

In another aspect, the present invention is directed to a method oftreating anaphylaxis comprising administering to a subject in needthereof an epinephrine spray formulation of the present invention,preferably administration occurs via the intranasal route or sublingualroute and wherein, optionally, the subject is suffering from seasonalallergies.

In another aspect, the present invention is directed to a method oftreating anaphylaxis comprising administering to a subject in needthereof an epinephrine spray formulation of the present invention viaunit dose or a multi-dose device that delivers more than one dose of theformulation, preferably via a bi-dose device that delivers two doses ofthe formulation.

In another aspect the present invention is directed to a method oftreating anaphylaxis comprising administering via an assembled device anepinephrine formulation of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Epinephrine plasma concentrations over first 6 hours postadministration.

FIG. 2. Epinephrine plasma concentrations over first 30 minutes postadministration.

FIG. 3. Semi-log plot of epinephrine plasma concentrations over first 6hours post administration.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Applicants discovered epinephrine spray formulations that have improvedbioavailability, a more rapid onset of action, and improved storagestability.

As used herein, “epinephrine” refers to the base.

As used herein, “free of propellant” refers to a formulation that is notadministered using compressed gas.

As used herein, all numerical values relating to amounts, weights, andthe like, that are defined as “about” each particular value is plus orminus 10%. For example, the phrase “about 10% w/w” is to be understoodas “9% w/w to 11% w/w.” Therefore, amounts within 10% of the claimedvalue are encompassed by the scope of the claims.

As used herein “% w/w” and “percent w/w” refer to the percent weight ofthe total formulation.

As used herein the term “effective amount” refers to the amountnecessary to treat a patient in need thereof.

As used herein the term “treat”, “treating” or “treatment” refers toameliorating or inhibiting symptoms of type I allergies includinganaphylaxis.

As used herein the term “subject” refers, but is not limited to, aperson that is experiencing type I allergies including anaphylaxis.

As used herein the term “anaphylaxis” refers to an allergic reactioninvolving multiple organ systems in a subject upon contact with anallergen rather or not that allergen is identifiable.

As used herein the term “allergen” refers to any chemical capable ofcausing an immune system response in a subject including, but notlimited to, chemicals found in drugs, food, plants, insect bites, andinsect stings.

As used herein the term “seasonal allergies” refers to an allergicrhinitis. Seasonal allergies symptoms include, but are not limited to,itchy, watery eyes, sneezing, runny or stuffy nose, swollen nasalturbinates, itchy sinuses, throat or ear canals, ear congestion andpostnasal drainage.

As used herein “nasal congestion” refers to a symptom of swollen nasalturbinates.

As used herein the term “pharmaceutically acceptable” refers toingredients that are not biologically or otherwise undesirable foradministration to a living subject.

“Sublingual” refers to administration of a substance via the mouth insuch a way that the substance is rapidly absorbed via the blood vesselsunder the tongue.

“Intranasal” refers to administration of the composition to any portionof the nasal epithelium.

In one embodiment, the present invention is directed to epinephrinespray formulations comprising epinephrine, or a salt thereof.

Preferred epinephrine salts include citrate, hydrochloride, halide,sulfate, bitartrate, tartrate, phosphate, acetate, malate, maleate,succinate, ascorbate, carbonate, mesylate and lactate. One of skill inthe art could use other pharmaceutically acceptable epinephrine salts inthe formulations of the present invention. In a preferred embodiment,the formulations contain epinephrine or the pharmaceutically acceptablesalt equivalent to from about 0.1% to about 15% w/w epinephrine. In amore preferred embodiment, the formulation contains epinephrine or thepharmaceutically acceptable salt equivalent to from about 0.1% to about10% w/w of epinephrine. Other most preferred embodiments includeformulations which contain epinephrine or the pharmaceuticallyacceptable salt equivalent to from about 0.1% w/w to about 10% w/w. In amost preferred embodiment, the epinephrine concentration between 3% and10% w/w.

In another embodiment, the present invention is directed to epinephrinespray formulations comprising epinephrine, or a salt thereof, whereinthe formulation is free of a propellant.

In another embodiment, the present invention is directed to epinephrinespray formulations comprising epinephrine, or a salt thereof, and one ormore excipients selected from acids, solvents, stabilizers, permeationenhancers, viscosity modifiers, sweeteners, sweetness enhancers, pHmodifiers, isotonicity agents and flavoring agents.

In a preferred embodiment, the formulations of the present inventioncontain from about 1% to about 65% w/w of an acid, more preferably fromabout 1% to about 45% w/w. Acids suitable for use in the presentinvention include, but are not limited to, hydrochloric acid, malicacid, tartaric acid, citric acid, succinic acid and combinations thereofIn a preferred embodiment, the acid is hydrochloric acid or malic acid,even more preferably from about 0.1N to about 12N hydrochloric acid,even more preferably from about 0.5 to about 6 N hydrochloric acid, evenmore preferably from about 0.5 N to about 3 N hydrochloric acid and mostpreferably 0.5 N or 3 N hydrochloric acid.

In a preferred embodiment, the formulations of the present inventioncontain from about 1% to 99% w/w of a solvent preferably from about 30%to about 99% w/w of the solvent.

Solvents suitable for use in the present invention include, but are notlimited to, water, ethanol, glycerin, propylene glycol, polyethyleneglycol 400 and combinations thereof, more preferably water.

In a preferred embodiment, the formulations of the present inventioncontain from about 0.001% to about 10% w/w of a stabilizer, preferablyfrom about 0.005% to about 7.5% w/w, and even more preferably from about0.01% to about 5% w/w. Stabilizers suitable for use in the presentinvention include, but are not limited to, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), ascorbic acid, methionine, sodiumascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite,ascorbyl palmitate, thioglycerol, alpha tocopherol (vitamin E), cysteinehydrochloride, citric acid, ethylenediaminetetraacetic acid (“EDTA”),sodium citrate, propyl gallate, 8-hydroxyquinoline, boric acid,histidine and combinations thereof. In a preferred embodiment, thestabilizer is selected from sodium metabisulfite, sodium bisulfite,disodium EDTA, 8-hydroxyquinoline and combinations thereof. In an evenmore preferred embodiment the stabilizer is a combination of sodiumbisulfite, sodium metabisulfite, 8-Hydroxyquinoline and EDTA. In afurther preferred embodiment, the formulations of the present inventioncontain from about 0.005% to 0.5% w/w EDTA as the stabilizer. In a morepreferred embodiment, the formulations of the present invention containfrom about 0.01% to 0.1% EDTA as the stabilizer. In a most preferredembodiment, the formulations of the present invention contain about0.05% EDTA as the stabilizer. In a further preferred embodiment, theformulations of the present invention contain sodium bisulfite andsodium metabisulfite as the anti-oxidants at a concentration from aboutfrom about 0.005% to 5% w/w. In a more preferred embodiment, theformulations of the present invention contain sodium bisulfite or sodiummetabisulfite or a combination thereof as the anti-oxidants at aconcentration from about from about 0.05% to 1% w/w. In a more preferredembodiment, the formulations of the present invention contain sodiumbisulfite or sodium metabisulfite combination thereof as theanti-oxidants at a concentration from about from about 0.05% to about 1%w/w, more preferably from about 0.1% to about 0.75% w/w. In a mostpreferred embodiment, the formulations of the present invention containsodium bisulfite as the anti-oxidant at a concentration at about 0.15%or 0.3% or 0.5% or 0.75% w/w.

In some embodiments, the formulations of the present invention containfrom about 0.001% w/w to about 15% w/w of a permeation enhancer,preferably from about 0.03% w/w to about 12% w/w, and even morepreferably from about 0.05% to 10% w/w.

Permeation enhancers suitable for use in the present invention include,but are not limited to, caprylic acid, oleic acid, polysorbate 80,menthol, EDTA, disodium edetate, cetylpyridinium chloride, sodium laurylsulfate, citric acid, sodium desoxycholate, sodium deoxyglycolate,glyceryl oleate, L-lysine and combinations thereof. Preferred permeationenhancers are caprylic acid, menthol or a combination thereof.

Viscosity modifiers suitable for the present invention include, but arenot limited to, polyvinylpyrrolidone, carboxymethyl cellulose,hydroxypropylmethyl cellulose (“HPMC”), methyl cellulose, hydroxyethylcellulose, glycerin, polyvinyl alcohol and combinations thereof. In apreferred embodiment, the viscosity modifier is HPMC.

Sweeteners suitable for the present invention include, but are notlimited to, sucralose, sucrose, aspartame, saccharin, dextrose,mannitol, glycerin, xylitol and combinations thereof In a preferredembodiment, the sweetener is sucralose.

In some embodiments, the formulations of the present invention containfrom about 0.001% to about 1% of a sweetness enhancer. Sweetnessenhancers suitable for the present invention include, but are notlimited to, the ammonium salt forms of crude and refined GlycyrrhizicAcid. Magnasweet® products (available from Mafco Worldwide Corporation,Magnasweet is a registered trademark of Mafco Worldwide Corporation) usethe ammonium salt forms of crude and refined Glycyrrhizic Acid.Glycyrrhizic Acid is also available as a pure derivative in the sodiumand potassium salt forms.

In a preferred embodiment, the formulations of the present invention areat a pH from about 2.0 to about 5.5. In a more preferred embodiment theformulations of the present invention are at a pH from about 3.0 toabout 5.0. In a further preferred embodiment, the formulations of thepresent invention are at a pH from about 4.0 to about 5.0. In a mostpreferred embodiment the formulations of the present invention are at apH of 4.5. pH modifiers suitable for the present invention include, butare not limited to, hydrochloric acid, citric acid, fumaric acid, lacticacid, sodium hydroxide, sodium citrate, sodium bicarbonate, sodiumcarbonate, ammonium carbonate and combinations thereof.

Preservatives suitable for the present invention include, but are notlimited to, butyl paraben, methyl paraben, ethyl paraben, propylparaben, sodium benzoate, chlorobutanol, benzalkonium chloride, benzoicacid and combinations thereof In a preferred embodiment, thepreservative is benzalkonium chloride. In a more preferred embodimentthe benzalkonium chloride is at a concentration from about 0.01% toabout 0.02% w/w, more preferably 0.01% or 0.02% w/w.

Flavoring agents suitable for the present invention include, but are notlimited to, peppermint oil, menthol, spearmint oil, citrus oil, cinnamonoil, strawberry flavor, cherry flavor, raspberry flavor, orange oil anda combination thereof.

In preferred embodiment, the present invention is directed toepinephrine spray formulations comprising:

from about 2.8% to about 4% w/w epinephrine, or a salt thereof;

from about 32% to about 38% w/w hydrochloric acid with a normality from0.5 to 3N;

from about 10% to about 65% w/w ethanol;

from about 2% to about 38% w/w water;

about 5 w/w propylene glycol;

from about 0.1% to about 0.75% w/w sodium bisulfite;

about 0.05% w/w disodium EDTA;

optionally, a permeation enhancer selected from the group consisting offrom about 2% to about 10% w/w caprylic acid, from about 0.5% to about1.0% w/w menthol and a combination thereof; and

optionally, benzalkonium chloride at a concentration from about 0.01% toabout 0.02% w/w, wherein the formulation optionally has a pH of about4.5.

In another preferred embodiment, the present invention is directed toepinephrine spray formulations comprising:

about 3.24% w/w epinephrine, or a salt thereof;

about 36.2% w/w hydrochloric acid with a normality of 0.5;

about 40% w/w ethanol;

about 14.84% w/w water;

about 5% w/w propylene glycol;

about 0.01% w/w benzalkonium chloride; and

from about 0.15% to about 0.3% w/w sodium bisulfite,

wherein the formulation has a pH at about 4.5.

In another preferred embodiment, the present invention is directed tointranasal epinephrine spray formulations comprising:

about 3.117% w/w epinephrine, or a salt thereof;

about 34.8% w/w hydrochloric acid with a normality of 0.5;

about 20% w/w ethanol;

about 36.87% w/w water;

about 5% w/w propylene glycol;

about 0.01% w/w benzalkonium chloride;

from about 0.15% w/w sodium bisulfite to about 0.3% w/w sodiumbisulfite,

wherein the formulation has a pH at about 4.5.

In another preferred embodiment, the present invention is directed tointranasal epinephrine spray formulations comprising:

about 3.04% w/w epinephrine, or a salt thereof;

about 33.8% w/w hydrochloric acid with a normality of 0.5;

about 62.35% w/w water;

about 0.01% w/w benzalkonium chloride;

from about 0.15% w/w sodium bisulfite to about 0.3% w/w sodiumbisulfite,

wherein the formulation has a pH at about 4.5.

An epinephrine spray formulation comprising:

about 2.96% w/w epinephrine base;

about 32.93% w/w hydrochloric acid with a normality of about 0.5N;

about 0.05% w/w edetate disodium dihydrate;

about 0.15% w/w sodium bisulfite;

about 0.01% w/w benzalkonium chloride;

about 0.6% w/w sodium chloride; and

about 63.30% w/w water, wherein the formulation has a pH at about 4.5.

An epinephrine spray formulation comprising:

about 3.18% w/w epinephrine base;

about 35.47% w/w hydrochloric acid with a normality of about 0.5N;

about 0.05% w/w edetate disodium dihydrate;

about 0.15% w/w sodium bisulfite;

about 0.01% w/w benzalkonium chloride;

about 5% w/w propylene glycol;

about 40.0% w/w ethanol; and

about 16.14% w/w water, wherein the formulation has a pH at about 4.5.

An epinephrine spray formulation comprising:

about 5.923% w/w epinephrine base;

about 16.46% w/w hydrochloric acid with a normality of about 2N;

about 0.05% w/w edetate disodium dihydrate;

about 0.15% w/w sodium bisulfite;

about 0.01% w/w benzalkonium chloride;

about 0.6% w/w sodium chloride; and

about 76.81% w/w water, wherein the formulation has a pH at about 4.5.

An epinephrine spray formulation comprising:

about 5.923% w/w epinephrine base;

about 16.46% w/w hydrochloric acid with a normality of about 2N;

about 0.05% w/w edetate disodium dihydrate;

about 0.30% w/w sodium bisulfite;

about 0.01% w/w benzalkonium chloride;

about 0.6% w/w sodium chloride; and

about 76.66% w/w water, wherein the formulation has a pH at about 4.5.

An epinephrine spray formulation comprising:

about 6.356% w/w epinephrine base;

about 17.74% w/w hydrochloric acid with a normality of about 2N;

about 0.05% w/w edetate disodium dihydrate;

about 0.15% w/w sodium bisulfite;

about 0.01% w/w benzalkonium chloride;

about 40.0% w/w ethanol;

about 5% w/w propylene glycol

about 30.70% w/w water, wherein the formulation has a pH at about 4.5.

An epinephrine spray formulation comprising:

about 6.356% w/w epinephrine base;

about 17.74% w/w hydrochloric acid with a normality of about 2N;

about 0.05% w/w edetate disodium dihydrate;

about 0.30% w/w sodium bisulfite;

about 0.01% w/w benzalkonium chloride;

about 40.0% w/w ethanol;

about 5% w/w propylene glycol

about 30.55% w/w water, wherein the formulation has a pH at about 4.5.

An epinephrine spray formulation comprising:

about 8.885% w/w epinephrine base;

about 24.70% w/w hydrochloric acid with a normality of about 2N;

about 0.05% w/w edetate disodium dihydrate;

about 0.15% w/w sodium bisulfite;

about 0.01% w/w benzalkonium chloride;

about 0.6% w/w sodium chloride; and

about 65.61% w/w water, wherein the formulation has a pH at about 4.5.

An epinephrine spray formulation comprising:

about 8.885% w/w epinephrine base;

about 24.70% w/w hydrochloric acid with a normality of about 2N;

about 0.05% w/w edetate disodium dihydrate;

about 0.45% w/w sodium bisulfite;

about 0.01% w/w benzalkonium chloride;

about 0.6% w/w sodium chloride; and

about 65.31% w/w water, wherein the formulation has a pH at about 4.5.

An epinephrine spray formulation comprising:

about 9.534% w/w epinephrine base;

about 26.60% w/w hydrochloric acid with a normality of about 2N;

about 0.05% w/w edetate disodium dihydrate;

about 0.15% w/w sodium bisulfite;

about 0.01% w/w benzalkonium chloride;

about 40.0% w/w ethanol;

about 5% w/w propylene glycol

about 18.65% w/w water, wherein the formulation has a pH at about 4.5.

An epinephrine spray formulation comprising:

about 9.534% w/w epinephrine base;

about 26.60% w/w hydrochloric acid with a normality of about 2N;

about 0.05% w/w edetate disodium dihydrate;

about 0.15% w/w sodium bisulfite;

about 0.01% w/w benzalkonium chloride;

about 40.0% w/w ethanol;

about 5% w/w propylene glycol

about 18.35% w/w water, wherein the formulation has a pH at about 4.5.

In another embodiment, administration to a human exposed to an allergenof 6 milligrams of epinephrine in the formulation #C1 of Table 62 belowproduced an epinephrine plasma concentration more than 100 picograms permilliliter at about 1-minute post administration.

In another embodiment, administration to a human not exposed to anallergen of 6 milligrams of epinephrine in the formulation #C1 of Table62 below produced an epinephrine plasma concentration more than 100picograms per milliliter at about 3-minutes post administration.

In another embodiment, administration to a human exposed to an allergenof 6 milligrams of epinephrine in the formulation #C2 of Table 62 belowproduced an epinephrine plasma concentration more than 100 picograms permilliliter at about 1-minute post administration.

In another embodiment, administration to a human exposed to an allergenof 6 milligrams of epinephrine in the formulation #C2 of Table 62 belowproduced an epinephrine plasma concentration more than 290 picograms permilliliter at about 1-minute post administration.

In another embodiment, administration to a human not exposed to anallergen of 6 milligrams of epinephrine in the formulation #C2 of Table62 below produced an epinephrine plasma concentration more than 100picograms per milliliter at about 3-minutes post administration.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 3 cm wherein themean DV (10) is from about 15 to about 18 microns during administration.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 3 cm wherein themean DV (50) is from about 30 to about 34 microns during administration.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 3 cm wherein themean DV (90) is from about 120 to about 230 microns duringadministration.

In another embodiment, the formulations of the present invention arecapable of producing a spray span ((Dv90-Dv10)/Dv50) at 3 cm of fromabout 3 to about 7.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 6 cm wherein themean DV (10) is from about 22 to about 25 microns during administration.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 6 cm wherein themean DV (50) is from about 36 to about 41 microns during administration.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 6 cm wherein themean DV (90) is from about 59 to about 231 microns duringadministration.

In another embodiment, the formulations of the present invention arecapable of producing a spray span ((Dv90-Dv10)/Dv50) at 6 cm of fromabout 1 to about 6.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 3 cm wherein the Dmin is fromabout 18 to about 23 millimeters during administration.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 3 cm wherein the Dmax is fromabout 29 to about 33 millimeters during administration.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 3 cm wherein the ovality ratiois from about 1.4 to about 1.7 during administration.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 6 cm wherein the Dmin is fromabout 26 to about 33 millimeters during administration.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 6 cm wherein the Dmax is fromabout 47 to about 52 millimeters during administration.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 6 cm wherein the ovality ratiois from about 1.6 to about 1.9 during administration.

In another embodiment, the formulations of the present invention arecapable of producing a plume geometry at 3 cm wherein the angle is fromabout 49° to about 64°.

In another embodiment, the formulations of the present invention arecapable of producing a plume geometry at 3 cm wherein the width is fromabout 27 to about 38 millimeters.

In another embodiment, the formulations of the present invention arecapable of producing a plume geometry at 3 cm wherein the angle is fromabout 37° to about 44°.

In another embodiment, the formulations of the present invention arecapable of producing a plume geometry at 3 cm wherein the width is fromabout 37 to about 44 millimeters.

In one embodiment, the present invention is directed to a method oftreating anaphylaxis comprising administering via an assembled device anepinephrine formulation comprising from about 0.1% w/w to about 15% w/wepinephrine or a salt thereof and from about 1% to about 80% w/w water,wherein the formulation has a pH from about 2 to about 5.5.

In a preferred embodiment, the assembled device comprises a reservoir, aplunger, a cannula, a spray pin, a reservoir holder and an actuator or areservoir, a piston and a swirl chamber.

In another preferred embodiment, the assembled device delivers one ormore doses of the epinephrine formulation.

In another preferred embodiment, the assembled device is a unit-dosedevice that delivers one dose of the epinephrine formulation upon asingle actuation and comprises a single reservoir containing not morethan 250 μL of the epinephrine formulation, preferably about 237 μL ornot more than 140 μL, preferably about 127 μL.

In another preferred embodiment, the assembled device is a unit-dosedevice that delivers about 200 μL or about 100 μL of the pharmaceuticalformulation upon a single actuation.

In another preferred embodiment, the assembled device is a bi-dosedevice that delivers two doses of the epinephrine formulation upon twoactuations and delivers about 100 of the epinephrine formulation peractuation.

In another preferred embodiment, the assembled device is a multi-dosedevice that delivers multiple doses of the epinephrine formulation uponmultiple actuations and delivers about 100 μL of the pharmaceuticalsolution per actuation.

The disclosed embodiments are simply exemplary embodiments of theinventive concepts disclosed herein and should not be considered aslimiting, unless the claims expressly state otherwise.

The following examples are intended to illustrate the present inventionand to teach one of ordinary skill in the art how to use theformulations of the invention. They are not intended to be limiting inany way.

EXAMPLES Example 1

An epinephrine spray was prepared as follows using the components andamounts listed in Table 1 below. All of the solvents were purged withnitrogen prior to use. Excipients including 0.5 N hydrochloric acid(“HCl”), malic acid, ethanol and propylene glycol, EDTA, sodiumchloride, sodium bisulfate, sodium metabisulfite, and 8-hydroxyquinolinewere dissolved in water while stirring at room temperature. Epinephrinebase was then added to the excipient solution. Finally, sodium hydroxide(“NaOH”)/hydrochloric acid (HCl)) was used to adjust final pH.

TABLE 1 Epinephrine Formulations % w/w #1 #2 #3 #4 #5 #6 #7 #8 #9 #10#11 Epinephrine base 1.0 1.0 1.0 1.0 1.0 7.5 1 3.0 3.0 3.0 3.0 HCl(0.5N) 10.66 10.66 10.66 10.66 10.66 — 11.35 — 32.6 32.6 32.6 EDTA 0.050.05 0.05 0.05 0.05 — — — 0.05 0.05 0.05 Sodium 0.01 0.015 0.02 0.0250.025 0.25 0.025 0.04 — — — metabisulfite sodium bisulfite 0.01 0.0150.02 0.025 0.025 — 0.025 0.05 0.2 0.2 Propylene Glycol — — — — — — — — —— 5 Menthol — — — — — — — — — — 5 Chlorobutanol — — — — — — — — — 0.5 —Sucralose — — — — — — — — — 0.5 0.5 8- — — — — 0.02 — — — — — —Hydroxyquinoline Ethanol — — — — — 15 — — — 50 Malic Acid — — — — — 2.0— 1.65 — — — Water 88.27 88.26 88.25 88.24 88.22 79.75 87.6 95.31 64.363.15 4.15 100 100 100 100 100 100 100 100 100 100 100 pH adjusted withpH pH pH pH pH pH pH pH pH pH pH NaOH 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.54.5 4.5 4.5

Example 2

The formulations listed in Table 1 were subjected to stability at 40°C.±2° C./75%±5% relative humidity and 25° C.±2° C./60%±5% relativehumidity. The stability of the formulations was analyzed at specifiedtime points by evaluating their potency (assay value) and impuritylevels. Assay and impurities were detected using high-performance liquidchromatography with an ultraviolet detector. The assay was performed at280 nm and indicated as a % of initial concentration. For allimpurities, analysis was performed at 210 nm and 280 nm and expressed asa % area. Amounts of particular impurities are listed in Tables 2 to 20as a percentage of area of each formulation along with amount of totalimpurities. Relative retention time (“RRT”) is given for each impurity.“ND” indicates that the impurity was not detected. “BQL” indicatespurity is below quantification limit.

TABLE 2 Stability Data for Epinephrine Spray Formulation #1 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #1 RRT 0Week 2 Weeks 4 Weeks Appearance Clear Clear Clear Assay (% of initialconc.) 100.00  97.94  95.80  % Racemization 0.60 0.93 1.54 pH 4.50 3.523.29 % Impurity F 0.19 0.13 1.07 1.51 % Synephrine 1.26 ND ND ND %Epinephrone 1.36 ND ND ND % Methoxy 1.88 0.07 0.07 0.07 % UnknownImpurity 0.21 ND 0.10 0.15 0.23 ND ND 0.02 3.11 ND BQL 0.03 3.26 ND BQL0.02 % Total Impurities 0.20 1.24 1.80

TABLE 3 Stability Data for Epinephrine Spray Formulation #2 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #2 RRT 0Week 2 Weeks 4 Weeks Appearance Clear Clear Clear Assay (% of initialconc.) 100.00  96.02  97.32  % Racemization 0.60 0.91 1.77 pH 4.50 3.393.14 % Impurity F 0.19 0.14 1.27 1.91 % Synephrine 1.26 ND ND ND %Epinephrone 1.38 ND ND BQL % Methoxy 1.88 0.07 0.07 0.07 % UnknownImpurity 0.21 ND 0.10 0.11 0.23 ND ND BQL 3.26 ND ND ND % TotalImpurities 0.21 1.44 2.09

TABLE 4 Stability Data for Epinephrine Spray Formulation #3 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #3 RRT 0Week 2 Weeks 4 Weeks 8 Weeks 3 Months Appearance Clear Clear Clear ClearClear Assay (% of initial conc.) 100.00  98.22  96.87  94.56  93.27  %Racemization 0.60 1.01 1.48 3.67 4.23 pH 4.50 3.37 3.14 3.01 — %Impurity F 0.19 0.13 1.27 2.19 3.05 3.18 % Synephrine 1.26 ND ND ND NDND % Epinephrone 1.36 ND ND BQL BQL BQL % Methoxy 1.88 0.07 0.07 0.070.07 0.07 % Unknown Impurity 0.21 ND 0.08 0.07 0.08 0.24 3.11 ND ND BQLBQL BQL 3.26 ND ND BQL BQL BQL % Total Impurities 0.20 1.42 2.33 3.203.49

TABLE 5 Stability Data for Epinephrine Spray Formulation #4 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation 0 1 2 4 6 83 4 #4 RRT Week Week Weeks Weeks Weeks Weeks Months Months AppearanceClear Clear Clear Clear Clear Clear Clear Clear Assay (% of 100.0  100.7   98.54  98.35  96.02  94.44  92.60  89.34  initial conc.) % 0.600.68 — — 3.41 3.46 5.75 9.20 Racemization % Impurity F 0.19 0.15 0.781.29 2.33 3.16 3.83 4.36 4.65 % Synephrine 1.26 ND ND ND ND ND ND ND ND% 1.36 ND ND ND BQL BQL BQL BQL BQL Epinephrone % Methoxy 1.88 0.08 0.080.08 0.08 0.08 0.08 0.08 0.09 % Unknown 0.21 ND ND 0.05 0.08 0.07 0.090.22 0.23 Impurity 3.11 ND ND ND BQL BQL BQL BQL 0.05 3.26 ND ND ND BQLBQL BQL BQL BQL % Total 0.23 0.86 1.42 2.49 3.31 4.00 4.66 5.02Impurities

TABLE 6 Stability Data for Epinephrine Spray Formulation #5 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #5 RRT 0Week 2 Weeks 4 Weeks 8 Weeks 3 Months Appearance Clear Clear Clear ClearClear Assay (% of initial conc.) 100.00  98.36  96.88  95.35  93.34  %Racemization 0.60 0.85 1.08 2.63 4.23 pH 4.50 3.64 3.37 3.20 — %Impurity F 0.19 0.15 1.48 2.50 3.50 3.75 % Synephrine 1.26 ND ND ND NDND % Epinephrone 1.36 ND ND BQL BQL BQL % Methoxy 1.88 0.07 0.07 0.070.07 0.07 % Unknown Impurity 0.21 ND 0.10 0.11 0.15 0.35 0.88 ND ND NDND BQL 3.11 ND ND BQL BQL BQL 3.26 ND ND BQL BQL BQL % Total Impurities0.22 1.65 2.68 3.72 4.17

TABLE 7 Stability Data for Epinephrine Spray Formulation #6 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #6 RRT 0Week 2 Weeks 1 Month Appearance Clear Clear Clear Assay (% of initialconc.) 100.00  97.75  95.95  % Impurity F 0.19 0.15 2.38 4.04 %Synephrine 1.26 ND ND ND % Epinephrone 1.36 ND BQL BQL % Methoxy 1.88BQL BQL BQL % Unknown Impurity 0.21 ND 0.05 0.08 % Total Impurities 0.152.43 4.08

TABLE 8 Stability Data for Epinephrine Spray Formulation #7 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #7 RRT 0Week 2 Weeks 4 Weeks Appearance Clear Clear Clear % Impurity F 0.19 0.321.85 2.75 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 ND ND ND %Methoxy 1.88 0.07 0.07 0.07 % Unknown Impurity 0.21 0.17 0.36 0.44 %Total Impurities 0.56 2.28 3.26

TABLE 9 Stability Data for Epinephrine Spray Formulation #8 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #8 RRT 0Week 2 Weeks Appearance Clear Light Brown Assay (% of initial conc.)100.00  95.55  % Racemization 0.63 0.62 % Impurity F 0.19 0.22 1.56 %Synephrine 1.26 ND ND % Epinephrone 1.36 ND ND % Methoxy 1.88 0.07 0.07% Unknown Impurity 0.21 ND 0.12 0.26 ND BQL 0.88 ND BQL 3.11 ND BQL 3.26ND BQL % Total Impurities 0.29 1.75

TABLE 10 Stability Data for Epinephrine Spray Formulation #9 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #9 RRT 0Week 1 Week 4 Weeks Appearance Clear Clear Clear Assay (% of initialconc.) 100.00  100.76  99.73  % Racemization 0.60 0.68 — % Impurity F0.19 0.15 0.84 1.86 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 ND NDND % Methoxy 1.88 0.07 0.07 0.07 % Unknown Impurity 0.21 ND ND 0.06 3.11ND BQL 0.09 3.26 ND BQL 0.08 % Total Impurities 0.22 0.91 2.16

TABLE 11 Stability Data for Epinephrine Spray Formulation #10 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #10 RRT 0Week 1 Week Appearance Clear Clear Assay (% of initial conc.) 100.00 100.76  % Racemization 0.60 0.68 % Impurity F 0.19 0.12 2.89 %Synephrine 1.26 ND ND % Epinephrone 1.36 ND ND % Methoxy 1.88 0.07 0.07% Unknown Impurity 0.21 ND BQL 3.11 ND BQL 3.26 ND BQL % TotalImpurities 0.19 2.96

TABLE 12 Stability Data for Epinephrine Spray Formulation #11 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #11 RRT 0Week 1 Week Appearance Clear Clear Assay (% of initial conc.) 100.00 100.76  % Racemization 0.60 0.68 % Impurity F 0.19 0.12 0.90 %Synephrine 1.26 ND ND % Epinephrone 1.36 ND ND % Methoxy 1.88 0.07 0.07% Unknown Impurity 0.21 ND BQL 3.11 ND BQL 3.26 ND BQL % TotalImpurities 0.19 0.97

TABLE 13 Stability Data for Epinephrine Spray Formulation #1 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #1 RRT 0Week 1 Month 3 Months Appearance Clear Clear Clear Assay (% of initialconc.) 100.00  97.91  97.32  % Racemization 0.60 0.76 0.93 % Impurity F0.19 0.13 0.53 1.04 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 ND NDND % Methoxy 1.88 0.07 0.07 0.07 % Unknown Impurity 0.21 ND 0.05 0.193.11 ND ND BQL 3.26 ND ND BQL % Total Impurities 0.20 0.65 1.30

TABLE 14 Stability Data for Epinephrine Spray Formulation #2 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #2 RRT 0Week 1 Month 3 Months Appearance Clear Clear Clear Assay (% of initialconc.) 100.00  97.56  96.88  % Racemization 0.60 0.78 1.01 % Impurity F0.19 0.14 0.55 1.25 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 ND NDND % Methoxy 1.88 0.07 0.07 0.07 % Unknown Impurity 0.21 ND 0.08 0.183.11 ND ND BQL 3.26 ND ND BQL % Total Impurities 0.21 0.70 1.50

TABLE 15 Stability Data for Epinephrine Spray Formulation #3 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #3 RRT 0Week 1 Month 3 Months Appearance Clear Clear Clear Assay (% of initialconc.) 100.00  99.32  98.16  % Racemization 0.60 0.75 0.84 % Impurity F0.19 0.13 0.52 1.29 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 ND NDND % Methoxy 1.88 0.07 0.07 0.07 % Unknown Impurity 0.21 ND BQL 0.093.11 ND ND BQL 3.26 ND ND BQL % Total Impurities 0.20 0.59 1.45

TABLE 16 Stability Data for Epinephrine Spray Formulation #4 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 3 4 8 3 6 25° C. Formulation#4 RRT 0 Week Weeks Weeks Weeks Months Months Appearance Clear ClearClear Clear Clear Clear Assay (% of initial 100.00  100.76  99.79 99.31  99.09  98.69  conc.) % Racemization 0.60 0.68 — 0.91 0.97 — %Impurity F 0.19 0.15 0.41 0.50 1.01 1.46 2.39 % Synephrine 1.26 ND ND NDND ND ND % Epinephrone 1.36 ND ND ND ND BQL BQL % Methoxy 1.88 0.08 0.080.08 0.08 0.08 0.08 % Unknown Impurity 0.21 ND 0.05 0.06 0.06 0.11 0.103.02 ND ND ND ND ND 0.12 3.11 ND ND ND ND ND 0.12 3.26 ND ND ND ND ND0.10 % Total Impurities 0.23 0.54 0.64 1.15 1.65 2.91

TABLE 17 Stability Data for Epinephrine Spray Formulation #5 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #5 RRT 0Week 1 Month 3 Months Appearance Clear Clear Clear Assay (% of initialconc.) 100.00  98.40  97.29  % Racemization 0.60 0.77 0.84 % Impurity F0.19 0.15 0.67 1.41 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 ND NDND % Methoxy 1.88 0.07 0.07 0.07 % Unknown Impurity 0.21 ND 0.05 0.183.11 ND ND BQL 3.26 ND ND BQL % Total Impurities 0.22 0.79 1.66

TABLE 18 Stability Data for Epinephrine Spray Formulation #6 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #6 RRT 0Week 2 Weeks 1 Month 6 Months Appearance Clear Clear Clear Clear Assay(% of initial conc.) 100.00  100.25  99.75  94.80  % Impurity F 0.190.15 0.45 0.76 2.93 % Synephrine 1.26 ND ND ND ND % Epinephrone 1.36 NDBQL BQL BQL % Methoxy 1.88 BQL BQL BQL BQL % Unknown Impurity 0.21 ND NDBQL 0.30 0.26 ND ND ND 0.13 0.88 ND ND ND 0.15 2.58 ND ND ND 0.10 3.11ND ND ND 0.24 3.26 ND ND ND 0.17 % Total Impurities 0.15 0.45 0.76 4.02

TABLE 19 Stability Data for Epinephrine Spray Formulation #8 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #8 RRT 0Week 1 Month Appearance Clear Clear Assay (% of initial conc.) 100.00 99.21  % Racemization 0.63 0.66 % Impurity F 0.19 0.22 0.64 % Synephrine1.26 ND ND % Epinephrone 1.36 ND ND % Methoxy 1.88 0.07 0.07 % UnknownImpurity 0.21 ND 0.06 3.11 ND BQL 3.26 ND BQL % Total Impurities 0.290.77

TABLE 20 Stability Data for Epinephrine Spray Formulation #9 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #9 RRT 0Week 1 Month 6 Months Appearance Clear Clear Clear Assay (% of initialconc.) 100.00  99.64  98.88  % Impurity F 0.19 0.15 0.52 1.71 %Synephrine 1.26 ND ND ND % Epinephrone 1.36 ND ND ND % Methoxy 1.88 0.080.07 0.07 % Unknown Impurity 0.21 ND 0.05 0.07 3.11 ND BQL 0.09 3.26 NDBQL 0.08 % Total Impurities 0.23 0.64 2.02

Formulations #1-#5 had less than 3% total impurities after 4 Weeks (1Month) at 40° C.±2° C./75%±5% Relative Humidity and less than 1% totalimpurities after 4 Weeks (1 Month) at 25° C.±2° C./60%±5% relativehumidity. Of Formulations #6-#8, only Formulation #8 was analyzed at 4Weeks or later at 40° C. where 4.68% total impurities were found.Formulation #9 exhibited total impurities of 2.17% at 4 weeks 40° C.Formulation # 11 exhibited total impurities of 1% at one week 40° C. Thesuperior and surprising stability characteristics of the formulations ofthe present invention will allow the formulations to be effective whenused by patients.

When compared with formulation 4, formulation 7 showed a fastergeneration of impurities and was not stable for more than a month at 40°C. Formulation 4 was stable for 4 months when stored at 40° C. whichindicates that EDTA increases the stability of epinephrine formulations.

Example 3

Formulation #4 was further tested for stability during freeze-thawcycling. Specifically, Formulation #4 was run through 3 cycles of −20°C. for 48 hours and then 25° C. for 48 hours, where the physicalappearance of the formulation was recorded. The formulation remainedclear and colorless throughout the entire freeze-thaw cycling indicatinga stable formulation throughout.

Example 4

In order to determine the spray profile of Formulation #4, it wassubjected to standardized droplet testing. A challenge of creating anepinephrine spray formulation is that it must be capable of producingspray droplets that are over 10 microns in diameter. Spray droplets of10 microns or smaller could be inhaled into the lungs.

Droplet analysis was conducted using standard laser analysis proceduresknown by those of skill in the art. Droplet size distribution (Dv₁₀,Dv₅₀, Dv₉₀, and Span) was tested at two distances, 3 cm and 6 cm. Dv₁₀refers to the droplet size at which 10% of the volume is smaller; Dv₅₀refers to the median droplet size; Dv₉₀ refers to droplet size for which90% of the total volume is smaller; Span refers to distribution span(Dv90-Dv10)/Dv50. %<10 μm refers to the percentage of the total volumethat is made up of droplets less than 10 μm in diameter.

Spray pattern, specifically Dmin, Dmax, and ovality ratio were tested attwo distances, 3 cm and 6 cm. Dmin refers to the shortest diameter ofthe spray pattern in mm, Dmax refers to the widest diameter of the spraypattern in mm, and ovality ratio refers to the ratio of Dmax to Dmin.The spay pattern is measured by shining a laser sheet perpendicular tothe spray at a specific distance from the orifice. The ovality ratio isuseful as it provides information regarding the shape and density of thespray pump plume.

The results of these tests can be seen below in Tables 17 to 22.

TABLE 21 Droplet size distribution of Epinephrine Spray Formulation at 3cm Droplet Size DV₁₀ DV₅₀ DV₉₀ Distribution 3 cm (μm) (μm) (μm) % <10 μmSpan Min 15.8 30.84 124 0.05 3.145 Max 17.23 33.96 228.7 0.89 6.283 Mean16.34 32.88 177.9 0.473 4.93

TABLE 22 Droplet size distribution of Epinephrine Spray Formulation at 6cm Droplet Size DV₁₀ DV₅₀ DV₉₀ Distribution 6 cm (μm) (μm) (μm) % <10 μmSpan Min 22.72 36.07 59.52 0 1.017 Max 24.05 40.35 230.9 0 5.127 Mean23.2 38.48 121.5 0 2.49

TABLE 23 Spray pattern of Epinephrine Spray Formulation at 3 cm DminDmax Ovality Spray Pattern 3 cm (mm) (mm) ratio Min 18.9 29.8 1.415 Max22.2 32.1 1.696 Mean 20.4 31.1 1.53

TABLE 24 Spray pattern of Epinephrine Spray Formulation at 6 cm DminDmax Ovality Spray Pattern 6 cm (mm) (mm) ratio Min 26.5 47 1.68 Max32.2 54.2 1.852 Mean 29.1 51.4 1.768

TABLE 25 Plume geometry of Epinephrine Spray Formulation at 3 cm PlumeGeometry 3 cm Angle (°) Width (mm) Min 49.2 27.6 Max 63.4 37.8 Mean 55.432.2

TABLE 26 Plume geometry of Epinephrine Spray Formulation at 6 cm PlumeGeometry 6 cm Angle (°) Width (mm) Min 37.7 37.7 Max 43.5 43.5 Mean 40.740.7

Applicant found during testing that formulations of the presentinvention yielded desirable droplet sizes for spray administration. Thetesting also revealed that the formulation dose remains consistent whenadministered with a spray pump.

Example 5 Preparation of Additional Hydro-Alcoholic Epinephrine SprayFormulations

Additional epinephrine spray formulations were prepared using thecomponents and amounts listed in Table 27 below. All solvents werepurged with nitrogen prior to use. Excipients including 0.5 Nhydrochloric acid (“HCl”), ethanol, propylene glycol, EDTA, sodiumbisulfite, caprylic acid were dissolved in water while stirring at roomtemperature. Epinephrine base was then added to the excipient solution.Finally, sodium hydroxide (“NaOH”)/hydrochloric acid (“HCl”) was used toadjust final pH.

TABLE 27 Additional Hydro-alcoholic Epinephrine Spray Formulations % w/w#12 #13 #14 #15 #16 #17 #18 #19 #20 Epinephrine base 3.2 3.2 3.2 3.2 3.23.38 3.38 3.24 3.12 Hydrochloric acid (0.5N) 34.6 34.6 34.6 34.6 34.637.7 37.7 36.2 34.8 EDTA 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05Sodium bisulfite 0.1 0.15 0.20 0.25 0.30 0.15 0.15 0.15 0.15 PropyleneGlycol 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Caprylic acid — — — — — 2.010.0 — — Benzalkonium chloride — — — — — 0.02 0.02 0.01 0.01 Menthol 1.01.0 1.0 1.0 1.0 0.5 0.5 — — Sucralose 0.5 0.5 0.5 0.5 0.5 0.5 0.5 — —Ethanol 40.0 40.0 40.0 40.0 40.0 40.0 40.0 40.0 20.0 Water 15.55 15.5015.45 15.40 15.35 10.7 2.7 15.35 36.87 pH adjusted with 4.5 4.5 4.5 4.54.5 4.5 4.5 4.5 4.5 2NaOH/0.5N HCl

TABLE 28 Additional Aqueous based Epinephrine Spray Formulation % w/w#21 #22 #23 #24 #25 #26 Epinephrine 3.040 3.040 3.040 3.040 3.040 3.040base Hydrochloric 33.80 33.80 33.80 33.80 33.80 33.80 acid (0.5N) EDTA0.05 0.05 0.05 0.05 0.05 0.05 Sodium 0.150 0.250 0.5 1.00 2.00 5.00bisulfite Benzalkonium 0.01 0.01 0.01 0.01 0.01 0.01 chloride Sodium 0.60.6 0.6 0.6 0.6 0.6 Chloride Water 62.35 62.25 62.00 61.5 60.5 57.5 pHadjusted 4.5 4.5 4.5 4.5 4.5 4.5 with 2NaOH/ 0.5N HCl

TABLE 29 Additional Epinephrine (6 mg/spray) Formulations % w/w Function#27 #28 #29 #30 Epinephrine base Active 5.923 6.356 5.923 6.356Ingredient Benzalkonium chloride Preservative 0.010 0.010 0.010 0.010Sodium Chloride Tonicity 0.600 — 0.600 — Agent Sodium bisulfite Anti-0.150 0.150 0.300 0.300 Oxidant Edetate Disodium Chelating 0.050 0.0500.050 0.050 Dihydrate (EDTA) agent Hydrochloric acid pH modifier 16.46217.736 16.462 17.736 (2N) Purified Water Vehicle 76.805 30.698 76.65530.548 Dehydrated Alcohol Co-Solvent — 40.000 — 40.000 (Ethanol)Propylene Glycol Co-Solvent — 5.000 — 5.000 Solution containing pHAdjust Adjust Adjust Adjust 2.0N NaOH and adjustment to pH to pH to pHto pH 0.5N HCl 4.5 ± 0.1 4.5 ± 0.1 4.5 ± 0.1 4.5 ± 0.1

TABLE 30 Additional Epinephrine (9 mg/spray) Formulations % w/w Function#31 #32 #33 #34 Epinephrine base Active 8.885 9.534 8.885 9.534Ingredient Benzalkonium chloride Preservative 0.010 0.010 0.010 0.010Sodium Chloride Tonicity 0.600 — 0.600 — Agent Sodium bisulfite Anti-0.150 0.150 0.45 0.45 Oxidant Edetate Disodium Chelating 0.050 0.0500.050 0.050 Dihydrate (EDTA) agent Hydrochloric acid pH modifier 24.69526.603 24.695 26.603 (2N) Purified Water Vehicle 65.610 18.653 65.31018.353 Dehydrated Alcohol Co-Solvent — 40.000 — 40.000 (Ethanol)Propylene Glycol Co-Solvent — 5.000 — 5.000 Solution containing pHAdjust Adjust Adjust Adjust 2.0N NaOH and adjustment to pH to pH to pHto pH 0.5N HCl 4.5 ± 0.1 4.5 ± 0.1 4.5 ± 0.1 4.5 ± 0.1

TABLE 31 Epinephrine (3 mg/spray) Formulations % w/w Function #35 #36Epinephrine base Active 3.178 2.962 Ingredient Benzalkonium chloridePreservative 0.010 0.010 Sodium Chloride Tonicity — 0.6 Agent Sodiumbisulfite Anti- 0.150 0.150 Oxidant Edetate Disodium Chelating 0.0500.050 Dihydrate (EDTA) agent Hydrochloric acid pH modifier 35.471 32.936(0.5N) Purified Water Vehicle 16.141 63.298 Dehydrated AlcoholCo-Solvent 40.000 — (Ethanol) Propylene Glycol Co-Solvent 5.000 —Solution containing pH Adjust Adjust 2.0N NaOH and adjustment to pH topH 0.5N HCl 4.5 ± 0.1 4.5 ± 0.1

The formulations listed in Table 27 and Table 28 were filled in unitdose devices, packed into an oxygen impermeable pouches with oxygenscavengers, and then subjected to stability at 40° C.±2° C./75%±5%relative humidity and 25° C.±2° C./60%±5% relative humidity. Thestability of the formulations was analyzed at specified time points byevaluating their potency (assay value) and impurity levels. Assay andimpurities were detected using high-performance liquid chromatographywith an ultraviolet detector. The assay was performed at 280 nm andindicated as a % of initial concentration. For all impurities, analysiswas performed at 210 nm and 280 nm and expressed as a % area. Amounts ofparticular impurities are listed in Tables 32 to 55 as a percentage ofarea of each formulation along with amount of total impurities. Relativeretention time (“RRT”) is given for each impurity. “ND” indicates thatthe impurity was not detected. Any impurity which is less than 0.05% isindicated as BQL. NP refers to Not Performed.

TABLE 32 Stability Data for Epinephrine Spray Formulations # 12 to # 16stored at 25° C. ± 2° C./60% ± 5% Relative Humidity Stability @18 M 25°C./60% RH F # 12 F # 13 F # 14 F # 15 F # 16 RRT 0 Week 18 months 18Months 18 Months 18 months 18 months Appearance Clear Clear Clear ClearClear Clear % Impurity F 0.19 0.11 1.91 2.53 3.27 3.57  4.79* %Synephrine 1.26 ND ND ND ND ND ND % Epinephrone 1.36 ND BQL BQL BQL BQLBQL % Methoxy 1.90 0.07 0.08 0.08 0.07 0.07 0.08 % Unknown Impurities0.22 0.01 0.12 0.12 0.13 0.12 0.12 0.25 ND 0.09 BQL BQL ND 0.07 0.26 NDND ND ND ND ND 0.64 ND ND ND ND ND BQL 0.88 ND BQL BQL BQL BQL BQL 1.21ND 0.09 0.09 0.08 BQL 0.06 1.34 ND BQL 0.05 BQL BQL BQL 1.50 ND ND ND0.07 BQL BQL 1.51 ND 0.1  0.07 ND ND ND 2.43 ND ND ND ND 0.06 ND 2.44 NDND 0.07 0.08 ND ND 2.45 ND 0.11 ND ND ND ND 2.57 ND ND ND ND ND 0.062.71 ND ND ND ND ND ND 2.90 ND ND ND BQL ND ND 2.91 ND ND BQL ND ND ND2.93 ND 0.07 ND ND ND ND 2.96 ND ND ND ND ND ND 3.11 ND 0.05 BQL BQL BQLBQL 3.26 ND ND BQL ND ND ND Total Impurities 0.19 2.62 3.01 3.70 3.825.18

TABLE 33 Stability Data for Epinephrine Spray Formulation # 17 stored at25° C. ± 2° C./60% ± 5% Relative Humidity RRT 1 Month 2 Month AppearanceClear Clear % Impurity F 0.19 0.50 0.72 % Epinephrone 1.36 ND ND %Methoxy 1.90 0.07 0.07 % Unknown 1.08 0.14 0.08 Impurities % TotalImpurities 0.71 0.87

TABLE 34 Stability Data for Epinephrine Spray Formulation # 18 stored at25° C. ± 2° C./60% ± 5% Relative Humidity RRT 1 Month 2 MonthsAppearance Clear Clear Clear % Impurity F 0.19 0.57 0.75 % Epinephrone1.36 ND ND % Methoxy 1.90 0.07 0.07 1.08 0.08 0.14 1.12 BQL 0.07 % TotalImpurities 0.72 1.03

TABLE 35 Stability Data for Epinephrine Spray Formulations # 19 storedat 25° C. ± 2° C./60% ± 5% Relative Humidity Epinephrine RRT T = 0 1 M 3M 6 M 12 M 18 M Assay (%) 101.32  99.22  100.49  98.92  100.41  98.60 Appearance Clear, Clear, Clear, Clear, Clear, Clear, Colorless ColorlessColorless Colorless Colorless Colorless % Impurity F 0.19 0.16 0.47 1.032.37 5.38 7.44 % Epinephrone 1.34 ND BQL BQL BQL BQL BQL % Methoxy 1.770.07 0.06 0.06 0.06 0.05 0.06 Unknown Impurities 0.20 ND ND 0.06 0.150.08 0.09 (%) 0.21 ND ND ND ND 0.07 0.05 0.26 ND ND ND 0.08 0.16 0.201.06 ND ND ND ND ND 0.13 1.20 ND ND ND 0.09 0.05 0.05 2.50 ND ND ND NDBQL 0.06 Total impurities (%) 0.23 0.53 1.15 2.75 5.79 8.08

TABLE 36 Stability Data for Epinephrine Spray Formulation # 20 stored at25° C. ± 2° C./60% ± 5% Relative Humidity Epinephrine RRT T = 0 1M 3M 6MAssay (% LC) 103.9307 102.23  99.07  97.70  Appearance Clear, Clear,Clear, Clear, Colorless Colorless Colorless Colorless Imp-F 0.19 0.160.53 1.25 2.86 epinephrone 1.35 ND BQL BQL BQL Methoxy 1.78 0.06 0.060.06 0.06 Unknown 0.21 ND ND 0.05 0.05 Impurities 0.26 ND ND ND BQL 0.70ND BQL BQL BQL 0.83 ND BQL BQL ND 0.88 BQL BQL BQL ND 1.22 ND ND ND BQL1.41 ND ND BQL BQL 1.49 ND ND ND ND 1.51 BQL ND ND ND 1.55 ND BQL BQL ND2.55 ND BQL BQL ND 2.56 ND BQL BQL ND 2.61 ND BQL BQL ND 2.72 ND ND BQLBQL 2.80 ND ND BQL ND 2.87 ND BQL ND ND 2.96 ND BQL ND ND 3.09 BQL BQLND ND 3.22 ND ND BQL ND 3.45 ND ND BQL ND 3.73 ND ND ND BQL Totalimpurities 0.22 0.59 1.36 2.97 (%)

TABLE 37 Stability Data for Epinephrine Spray Formulation # 21 stored at25° C. ± 2° C./60% ± 5% Relative Humidity RRT T = 0 1 M 2 M 3 M 4 M 6 M8 M 12 M Assay 98.20  101.02  99.07  100.13  98.45  98.45  98.45  95.12 Appearance Clear, Clear, Clear, Clear, Clear, Clear, Clear, Clear,Colorless Colorless Colorless Colorless Colorless Colorless ColorlessColorless % Impurity F 0.19 0.16 0.72 1.38 1.99 2.54 4.30 5.40 7.05 %Epinephrone 1.34 ND BQL BQL BQL BQL BQL BQL BQL % Methoxy 1.77 0.06 0.060.06 0.06 0.06 0.05 0.05 0.05 Unknown 0.20 ND ND ND ND ND ND BQL BQLImpurities 0.66 ND ND ND ND ND ND ND 0.05 Total impurities 0.22 0.781.44 2.05 2.60 4.35 5.45 7.15 (%)

TABLE 38 Stability Data for Epinephrine Spray Formulations # 12 to 16stored at 40° C. ± 2° C./75% ± 5% Relative Humidity F# 12 F# 13 F# 14 F#15 F# 16 Epinephrine RRT 0 Week 2 Months 2 Months 2 Months 2 Months 2Months Assay 100.00  98.13  94.51  93.02  93.26  92.02  Appearance ClearClear Clear Clear Clear Clear % Impurity F 0.19 0.11 3.22 5.64 7.42 9.7 11.3  % Synephrine 1.26 ND ND ND ND ND ND % Epinephrone 1.36 ND BQL BQLBQL BQL BQL % Methoxy 1.90 0.07 0.06 0.06 0.06 0.06 0.06 % Unknown 0.22BQL 0.16 0.16 0.15 0.14 0.12 Impurities 0.25 ND 0.06 0.06 0.05 0.05 0.050.26 ND ND BQL BQL BQL BQL 0.88 ND ND BQL BQL BQL BQL 1.21 ND 0.06 0.060.05 BQL BQL 1.34 ND BQL BQL BQL BQL BQL 1.55 ND BQL BQL BQL BQL BQL2.57 ND 0.18 0.11 0.1 0.08 0.07 3.11 ND BQL BQL BQL BQL BQL 3.26 ND BQLBQL BQL BQL ND % Total 0.18 3.74 6.09 7.83 10.03  11.60  Impurities

TABLE 39 Stability Data for Epinephrine Spray Formulations # 17 storedat 40° C. ± 2° C./75% ± 5% Relative Humidity RRT 2 Weeks 4 Weeks 6 Weeks3 Months Physical Clear Clear Clear Clear appearance % Impurity F 0.191.02 2.03 3.01 5.11 % Epinephrone 1.36 ND ND BQL BQL % Methoxy 1.90 0.070.07 0.07 0.06 1.08 0.08 0.15 0.15 0.09 1.12 ND ND 0.15 0.15 1.21 ND BQL0.06 0.13 2.53 BQL BQL 0.05 0.15 2.58 ND ND BQL 0.06 3.04 ND ND BQL 0.06% Total 1.17 2.25 3.49 5.81 Impurities

TABLE 40 Stability Data for Epinephrine Spray Formulations # 18 storedat 40° C. ± 2° C./75% ± 5% Relative Humidity RRT 2 Weeks 1 Month 2Months Appearance Clear Clear Clear % Impurity F 0.19 0.93 2.16 3.71 %Epinephrone 1.36 ND BQL BQL % Methoxy 1.90 0.07 0.07 0.07 1.08 0.09 0.090.10 1.12 BQL 0.06 0.14 1.21 ND BQL 0.18 2.53 0.09 0.23 0.17 2.58 BQL0.08 0.07 3.04 BQL BQL 0.05 % Total Impurities 1.18 2.69 4.49

TABLE 41 Stability Data for Epinephrine Spray Formulation # 19 stored at40° C. ± 2° C./75% ± 5% Relative Humidity Epinephrine RRT 0 Month 1 M 2M 3 M 4 M 5 M 6 M 10 M Assay 101.32  101.11  97.06  95.85  96.08  96.52 95.58  NP Appearance Clear, Clear, Clear, Clear, Clear, Clear, Clear,Clear, colorless colorless colorless Light Light Light Light LightYellow Yellow Yellow Yellow Yellow Imp-F 0.19 0.16 1.92 4.25 6.42 7.207.28 7.22 7.61 epinephrone 1.34 ND BQL BQL BQL BQL BQL BQL BQL Methoxy1.77 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 Unknown Impurities 0.21 ND0.09 0.19 0.11 0.3 0.07 0.14 0.18 (%) 0.26 ND ND 0.14 0.21 0.31 0.320.31 0.52 0.52 ND ND ND ND BQL BQL BQL BQL 0.64 ND ND ND ND BQL ND ND ND0.79 ND ND ND BQL ND ND BQL BQL 0.88 ND BQL ND ND BQL BQL BQL BQL 1.17ND 0.06 0.07 0.05 0.09 0.08 ND ND 1.25 ND BQL BQL BQL BQL 0.07 0.07 0.071.38 ND BQL BQL BQL BQL BQL BQL BQL 1.55 ND ND ND BQL ND ND ND ND 1.68ND ND ND BQL BQL ND BQL BQL 1.73 ND ND ND BQL BQL BQL BQL BQL 1.99 ND NDND ND BQL BQL BQL BQL 2.07 ND ND ND ND BQL BQL BQL BQL 2.38 ND BQL ND NDND BQL ND ND 2.22 ND ND ND ND ND ND BQL BQL 2.44 ND ND ND ND ND ND BQLBQL 2.60 ND BQL 0.05 0.1 0.19 0.33 0.76 0.99 2.80 ND ND ND BQL ND ND NDND 2.86 ND BQL ND ND ND ND ND ND 2.98 ND BQL ND ND ND BQL ND ND 3.13 NDBQL ND ND ND ND ND ND 3.22 ND ND ND BQL ND ND ND ND 2.82 ND ND ND ND0.07 0.12 0.13 0.21 3.38 ND ND ND ND BQL ND ND ND 3.41 ND ND ND ND NDBQL ND ND 3.44 ND ND ND BQL 0.14 0.06 ND ND 3.51 ND ND ND ND ND ND 0.130.12 3.68 ND ND ND BQL BQL BQL 0.07 0.06 Total impurities (%) 0.23 2.134.76 6.95 8.36 8.39 8.89 9.82

TABLE 42 Stability Data for Epinephrine Spray Formulation # 20 stored at40° C. ± 2° C./75% ± 5% Relative Humidity Epinephrine RRT T = 0 1 M 2 M3 M 4 M 5 M 6 M Assay (%) 103.93  99.44  96.16  96.35  96.38  96.05 93.96  Appearance Clear, Clear, Clear, Clear, Clear, Clear, Clear,colorless colorless colorless Light Light Light Light Yellow YellowYellow Yellow % Impurity F 0.19 0.16 2.61 5.66 7.69 6.30 7.42 7.67 %Epinephrone 1.35 ND BQL BQL BQL BQL BQL BQL % Methoxy 1.78 0.06 0.070.06 0.06 0.06 0.07 0.07 Unknown 0.21 ND 0.08 0.10 0.09 0.29 0.10 0.13Impurities (%) 0.26 ND ND 0.06 0.12 0.17 0.18 0.19 0.70 ND BQL BQL BQLBQL ND BQL 0.88 BQL BQL BQL BQL BQL BQL BQL 1.13 ND ND ND ND ND 0.08 ND1.18 ND BQL BQL BQL 0.11 ND ND 1.21 ND ND ND ND ND ND 0.06 1.34 ND ND NDND BQL BQL ND 1.36 ND ND ND BQL BQL ND BQL 1.49 ND BQL ND ND ND ND ND1.42 ND ND ND BQL ND ND ND 1.51 BQL ND ND ND ND ND ND 1.55 ND BQL BQLBQL ND ND ND 1.58 ND ND ND ND 0.09 ND ND 1.64 ND ND ND BQL ND ND ND 1.73ND ND ND ND ND BQL 0.05 1.89 ND ND ND BQL ND BQL ND 2.00 ND ND ND ND BQL0.05 0.08 2.09 ND ND ND ND ND ND 0.08 2.21 ND ND ND ND ND ND 0.08 2.39ND BQL ND ND BQL BQL ND 2.44 ND ND ND ND ND ND 0.05 2.56 ND BQL ND ND NDBQL BQL 2.61 ND BQL BQL 0.07 ND ND ND 2.71 ND ND ND ND 0.39 0.54 1.102.87 ND BQL ND BQL BQL ND ND 2.96 ND BQL ND ND ND ND BQL 3.09 BQL BQL NDND ND ND ND 3.14 ND BQL ND ND ND ND ND 3.36 ND ND ND 0.14 0.16 0.16 0.173.48 ND ND ND ND 0.22 0.04 0.19 3.55 ND ND ND BQL BQL ND BQL 3.71 ND ND0.05 ND ND 0.05 0.08 3.83 ND ND ND ND ND ND BQL 4.34 ND ND ND ND ND NDBQL Total impurities 0.22 2.76 5.93 8.17 7.79 8.69 10.00  (%)

TABLE 43 Stability Data for Epinephrine Spray Formulation # 21 stored at40° C. ± 2° C./75% ± 5% Relative Humidity Epinephrine RRT T = 0 1 M 2 M3 M 4 M 5 M 8 M 12 M Assay (%) 98.20  94.84  94.14  95.37  95.07  95.87 95.18  96.1  Appearance Clear, Clear, Clear, Clear, Clear, Clear, Clear,Clear, colorless colorless Light Light Light Light Light Light YellowYellow Yellow Yellow Yellow Yellow % Impurity F 0.19 0.16 4.43 7.96 8.208.31 7.93 8.47 8.36 % Epinephrone 1.34 ND BQL BQL BQL BQL BQL BQL BQL %Methoxy 1.77 0.06 0.06 0.06 0.06 0.05 0.09 0.05 0.05 Unknown 0.20 ND0.06 ND ND 0.11 0.11 BQL BQL Impurities (%) 0.66 ND ND ND ND ND BQL BQLBQL 0.83 ND ND ND ND ND ND 0.05 ND 1.67 ND ND ND 0.15 0.14 0.14 0.110.12 1.70 ND ND ND ND ND ND ND 0.08 1.73 ND ND ND ND ND 0.07 0.06 0.131.81 ND ND ND ND ND ND 0.08 0.05 1.82 ND ND ND ND ND ND 0.06 BQL 1.92 NDND ND ND ND ND 0.08 0.31 1.95 ND ND ND ND ND ND 0.08 0.09 2.00 ND ND NDND ND ND 0.06 0.1  2.09 ND ND ND ND ND ND 0.09 0.27 2.27 ND ND ND ND NDND ND 0.06 2.40 ND ND ND ND ND ND 0.24 0.29 2.72 ND ND ND BQL BQL BQLBQL 0.08 2.79 ND ND ND 0.17 0.18 0.26 BQL 0.57 2.84 BQL BQL ND 0.05 ND0.12 0.12 0.2  2.87 ND ND ND ND 0.2  0.13 0.12 0.62 2.96 ND ND ND ND NDND ND 0.08 2.98 ND ND ND ND ND ND ND 0.11 3.06 ND ND ND ND ND ND ND 0.143.15 ND ND ND ND ND ND ND 0.08 3.18 ND ND ND ND ND ND ND 0.06 Totalimpurities 0.22 4.55 8.02 8.63 8.99 8.85 9.67 11.85  (%)

TABLE 44 Stability Data for Epinephrine Spray Formulation # 27 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1M 3M 4M AppearanceClear, Clear, Clear, Clear, colorless colorless Light Light YellowYellow Assay 101.98  101.74  NP NP % Impurity F 0.19 0.16 3.36 3.26 3.49% Epinephrone 1.34 BQL BQL BQL BQL % Methoxy 1.77 0.06 0.06 0.08 0.08Unknown 0.20 ND 0.05 0.05 0.06 (%)Impurities 1.12 ND ND 0.09 0.05 2.14ND ND ND 0.05 2.34 ND ND ND 0.06 2.89 ND ND ND 0.16 2.96 ND ND 0.50 0.482.99 ND ND 0.10 0.19 3.05 ND 0.38 0.46 0.43 Total impurities 0.22 3.854.54 5.05 (%)

TABLE 45 Stability Data for Epinephrine Spray Formulation # 28 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1M 3M 4M AppearanceClear, Clear, Clear, Clear, colorless colorless Light Light YellowYellow Assay 108.90  107.20  NP NP % Impurity F 0.19 0.16 1.75 3.15 3.61% Epinephrone 1.34 BQL BQL BQL BQL % Methoxy 1.77 0.06 0.06 0.08 0.08Unknown 0.20 ND 0.24 0.24 0.33 Impurities (%) 0.25 ND ND 0.09 0.09 2.50ND 0.10 0.25 0.83 2.96 ND ND 0.21 0.37 2.99 ND ND ND 0.05 3.05 ND 0.070.15 0.28 3.21 ND ND ND 0.27 Total impurities 0.22 2.22 4.17 5.91 (%)

TABLE 46 Stability Data for Epinephrine Spray Formulation # 29 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1M 3M 4M AppearanceClear, Clear, Clear, Clear, colorless colorless Light Light YellowYellow Assay 101.08  102.42  NP NP % Impurity F 0.19 0.16 6.12 8.87 8.86% Epinephrone 1.34 BQL BQL BQL BQL % Methoxy 1.77 0.06 0.06 0.06 0.08Unknown 0.20 ND BQL BQL BQL Impurities 0.25 ND ND ND ND 1.06 ND ND ND0.14 1.12 ND ND 0.09 0.09 1.99 ND ND 0.06 0.12 2.05 ND ND ND 0.14 2.15ND ND ND 0.08 2.34 ND ND ND 0.08 2.89 ND ND 0.11 0.23 2.96 ND ND 0.450.47 2.99 ND ND 0.13 0.27 3.05 BQL BQL 0.40 0.43 3.20 ND ND 0.15 0.23Total impurities 0.22 6.18 10.32  11.22  (%)

TABLE 47 Stability Data for Epinephrine Spray Formulation # 30 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1M 3M 4M AppearanceClear, Clear, Clear, Clear, colorless colorless Light Light YellowYellow Assay 106.62  107.37  NP NP % Impurity F 0.19 0.16 5.00 8.76 8.41% Epinephrone 1.34 BQL BQL BQL BQL % Methoxy 1.77 0.06 0.06 0.09 0.08Unknown 0.20 ND BQL 0.07 0.07 Impurities 0.25 ND ND 0.14 0.16 1.06 ND NDND 0.14 1.12 ND ND 0.05 BQL 2.50 ND 0.05 0.12 0.43 2.96 ND ND 0.06 0.292.99 ND ND ND 0.07 3.05 ND BQL 0.05 0.23 3.20 ND BQL 0.05 0.16 Totalimpurities 0.22 5.11 9.39 10.04  (%)

TABLE 48 Stability Data for Epinephrine Spray Formulation # 31 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1M 3M AppearanceClear, Clear, Clear, colorless colorless Light Yellow Assay 101.23 115.59  NP % Impurity F 0.19 0.16 2.75 2.35 % Epinephrone 1.34 BQL BQLBQL % Methoxy 1.77 0.06 0.06 0.09 Unknown 0.18 ND BQL BQL Impurities (%)1.12 ND ND 0.05 2.03 ND ND 0.05 2.79 ND ND BQL 2.86 ND ND 0.12 2.92 NDND 0.82 2.99 ND 0.05 0.14 3.05 ND 0.92 0.72 3.16 ND ND 0.08 Totalimpurities 0.22 3.78 4.42 (%)

TABLE 49 Stability Data for Epinephrine Spray Formulation # 32 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T0 1M 3M Appearance Clear,Clear, Clear, colorless colorless Light Yellow Assay 108.96  103.80  NP% Impurity F 0.19 0.16 1.89 2.50 % Epinephrone 1.34 BQL BQL BQL %Methoxy 1.77 0.06 0.06 0.09 Unknown 0.18 ND 0.11 0.08 Impurities 0.25 NDND BQL 1.12 ND ND 0.07 1.19 ND ND 0.05 2.48 ND 0.16 0.50 2.92 ND ND 0.493.00 ND 0.16 0.37 3.16 ND ND 0.16 Total impurities 0.22 2.38 4.31 (%)

TABLE 50 Stability Data for Epinephrine Spray Formulation # 33 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1M 3M AppearanceClear, Clear, Clear, colorless colorless Light Yellow Assay 100.05 99.36  NP % Impurity F 0.19 0.16 9.14 9.82 % Epinephrone 1.34 BQL BQLBQL % Methoxy 1.77 0.06 0.06 0.09 Unknown 0.18 ND BQL BQL Impurities (%)1.74 ND ND 0.60 1.98 ND ND 0.07 2.04 ND ND 0.07 2.32 ND ND 0.07 2.86 NDND 0.18 2.92 ND ND 0.70 2.95 ND ND 0.23 3.01 ND ND 0.62 3.16 ND ND 0.153.29 ND ND 0.05 Total impurities 0.22 9.20 12.65  (%)

TABLE 51 Stability Data for Epinephrine Spray Formulation # 34 stored at40° C. ± 2° C./75% ± 5% Relative Humidity Epinephrine RRT T = 0 1M 3MAppearance Clear, Clear, Clear, colorless colorless Light Yellow Assay113.33  112.55  NP % Impurity F 0.19 0.16 6.30 9.61 % Epinephrone 1.34BQL BQL BQL % Methoxy 1.77 0.06 0.06 0.08 Unknown 0.18 ND BQL 0.06Impurities (%) 0.25 ND ND 0.09 1.06 ND ND 0.16 1.12 ND ND 0.07 1.32 NDND BQL 2.32 ND ND BQL 2.55 ND 0.07 0.23 2.93 ND ND 0.34 2.96 ND ND 0.072.98 ND ND 0.08 3.02 ND 0.08 0.28 3.17 ND ND 0.08 Total impurities 0.226.51 11.15  (%)

TABLE 52 Stability Data for Epinephrine Spray Formulation # 35 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 2M 3M 6M Assay101.32  83.12  91.78  100.20  Appearance Clear, Clear, Clear, Clear,colorless colorless colorless colorless % Impurity F 0.19 0.16 4.56 6.407.56 % Epinephrone 1.34 ND BQL BQL BQL % Methoxy 1.77 0.07 0.06 0.050.05 Unknown 0.20 ND ND ND 0.13 Impurities (%) 0.21 ND 0.26 0.05 0.080.26 ND 0.13 0.12 0.30 1.19 ND 0.06 BQL BQL 1.71 ND BQL BQL 0.05 1.95 NDND ND 0.07 2.45 ND 0.06 0.05 0.73 2.92 ND ND ND 0.19 2.95 ND ND ND 0.132.97 ND ND ND 0.16 Total Impurities 0.23 5.13 6.67 9.45 (%)

TABLE 53 Stability Data for Epinephrine Spray Formulation # 36 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 2M 6M Assay 101.32 91.40  103.10  Appearance Clear, Clear, Clear, colorless colorlesscolorless % Impurity F 0.19 0.16 6.81 6.90 % Epinephrone 1.34 ND BQL BQL% Methoxy 1.77 0.07 0.06 0.05 Unknown 0.21 ND 0.09 0.07 Impurities (%)0.70 ND BQL ND 1.71 ND ND 0.07 1.92 ND ND 0.07 1.95 ND ND 0.05 2.00 NDND 0.05 2.09 ND ND 0.06 2.27 ND ND 0.05 2.41 ND ND 0.08 2.84 ND ND 0.192.90 ND ND 0.29 2.93 ND ND 0.31 2.98 ND ND 0.25 Total Impurities 0.236.96 8.49 (%)

TABLE 54 Stability Data for Epinephrine Spray Formulation # 35 stored at25° C. ± 2° C./60% ± 5% Relative Humidity RRT T = 0 3M 6M Assay 101.32 92.83  101.79  Appearance Clear, Clear, Clear, colorless colorlesscolorless % Impurity F 0.19 0.16 1.08 2.32 % Epinephrone 1.34 ND BQL BQL% Methoxy 1.77 0.07 0.05 0.06 Unknown 0.21 ND BQL 0.07 Impurities (%)0.26 ND ND ND 0.23 ND ND BQL 1.20 ND ND BQL 2.45 ND ND BQL TotalImpurities 0.23 1.13 2.45 (%)

TABLE 55 Stability Data for Epinephrine Spray Formulation # 36 stored at25° C. ± 2° C./60% ± 5% Relative Humidity RRT T = 0 3M 6M Assay 101.32 103.80  104.79  Appearance Clear, Clear, Clear, colorless colorlesscolorless % Impurity F 0.19 0.16 1.54 4.00 % Epinephrone 1.34 ND BQL BQL% Methoxy 1.77 0.07 0.06 0.05 Unknown 0.21 ND BQL BQL Impurities (%)0.72 ND BQL BQL 0.83 ND BQL ND 3.09 ND BQL 0.05 Total impurities 0.231.60 4.10 (%)

All formulas exemplified in Tables 27 to 31 above, remained clearthroughout stability testing. Formulations were filled in to unit dosespray devices under nitrogen blanket, and then subjected to acceleratedstability testing at 25° C.±2° C./60% ±5% and 40° C.±2° C./75%±5%without pouching (Formulations 12 to 18), while formulations (F# 19 to36) were subjected to accelerated stability testing under similarconditions with pouching containing oxygen scavenges. Formulation 13,un-pouched showed impurity F levels at 5.64% at 2M/40° C. Howeversimilar formulation 19, pouched, exhibited impurity F levels at 4.25% at2M/40° C. Stability data suggest that epinephrine spray formulationswhich are pouched with oxygen scavenges are more stable compare toun-pouched formulations. Both hydro-alcoholic and aqueous formulationsof present invention are stable at room temperature as well as 40° C.±2°C./75%±5.

For the Epinephrine 6 mg aqueous formulation in pouches, 3.49% and 8.86%of impurity F was observed after a period of 4 months at 40° C.±2°C./75% RH±5% RH for Formulations # 27 and 29 respectively. Totalimpurities for Formulations # 27 and 29 were found to be 5.05% and11.22% after a period of 4 months at 40° C.±2° C./75% RH±5% RH,respectively. In the case of hydro-alcoholic formulations of the samestrength in pouches, 3.61% and 8.41% of impurity F was observed afterthe same period for formulations # 28 and 30, respectively. Totalimpurities for Formulations # 28 and 30 were found to be 5.91% and10.04% after a period of 4 months at 40° C.±2° C./75% RH±5% RH,respectively.

For the Epinephrine 9 mg aqueous formulation in pouches, 2.35% and 9.82%of impurity F was observed after a period of 4 months at 40° C.±2°C./75% RH±5% RH for Formulations # 31 and 33 respectively. Totalimpurities for formulations # 31 and 33 were found to be 4.42% and12.65% after a period of 4 months at 40° C.±2° C./75% RH±5% RH,respectively. In the case of hydro-alcoholic formulations of the samestrength in pouches, 2.50% and 9.61% of impurity F was observed afterthe same period for Formulations # 32 and 34. Total impurities forFormulations # 32 and 34 were found to be 4.31% and 11.15% after aperiod of 4 months at 40° C.±2° C./75% RH±5% RH, respectively.

Example 6 Mini-Pig Pharmacokinetic Data for Epinephrine Formulations

Protocol design was a single-dose crossover study. Five healthy maleYucatan mini-pigs weighing approximately eighty to ninety-five kilogramseach were administered epinephrine formulations. The minipigs werefasted overnight till four hours' post administration. Each dosing wasfollowed by a washout period of at least one-week. Blood samples weretaken prior to administration and 2, 5, 10, 15, 20, 30, 45 min, 1, 1.5,2, 4, and 24 hours' post dose. Minipig plasma samples were measured forepinephrine concentrations via liquid chromatography-tandem massspectrometry.

The following pharmacokinetic parameters were calculated: peakconcentration in plasma (C_(max)), time to reach C. (T_(max)), and areaunder the concentration-time curve from time-zero to 24 hours postdose(AUC_(0-24h)).

The pharmacokinetic behavior of epinephrine formulations was evaluated.At 5 minutes after a single-dose intramuscular (IM) administration ofepinephrine in minipigs, the geometric mean plasma concentration ofepinephrine was 0.046 ng/mL. When epinephrine was formulated in #M1 andadministered intranasally, a more rapid absorption of epinephrine wasobserved. Specifically, #M1 showed a geometric mean epinephrine plasmaconcentration of 0.26 ng/mL at 5 minutes postdose. It was also notedthat a plasma concentration of 0.41 ng/mL was achieved as early as 2minutes after an intranasal administration of #M1. In addition, #M1showed a geometric mean Cmax of 1.01 ng/mL and a geometric meanAUC_(0-24h) of 161.0 ng*min/L.

TABLE 56 Epinephrine Formulations for Minipig Dosing Formulation #M1Epinephrine base 3.25 Dilute Hydrochloric acid 0.5N 36.2 BenzalkoniumChloride 0.01 Ethanol 40 Propylene Glycol 5 Sodium Bisulfite 0.15 EDTA0.05 Water 15.34 Total 100

-   Components: % w/w

TABLE 57 Plasma concentrations for epinephrine after administration toYucatan minipigs under fasted conditions. Formulation IM solution #M1Route of administration IM Intranasal Dose per animal (mg) 0.3 6Concentration @ 2 min (ng/mL) 0.036 0.41 Concentration @ 5 min (ng/mL)0.046 0.26 Concentration @ 10 min (ng/mL) 0.073 0.31 Concentration @ 15min (ng/mL) 0.103 0.17 Concentration @ 30 min (ng/mL) 0.100 0.19 T_(max)(min) 90 5 C_(max) (ng/mL) 0.25 1.01 AUC_(0-24 h) (ng*min/mL) 173.7161.0

-   Plasma concentration: geometric mean-   T_(max): median value-   C_(max) and AUC_(0-24h): geometric mean

Example 7 Rabbit Pharmacokinetic Data for Epinephrine Formulations

Protocol design was a single-dose non-crossover study. Pharmacokineticsof a number of epinephrine formulations were evaluated in healthy maleNew Zealand white rabbits weighing approximately two to three kilograms.For dosing of each formulation, five or six rabbits were used. Therabbits were fasted overnight till four hours' post administration.Blood samples were taken prior to administration and 5, 10, 15, 20, 30,40 min, 1, 1.5, 2, 4, and 5 hours' post dose. Rabbit plasma samples weremeasured for epinephrine concentrations via liquid chromatography-tandemmass spectrometry.

Formulation #R1-#R8 were provided in Table 43 and 44. Formulation #R9existed as a spray-dried powder of epinephrine bitartrate salt. For theevaluation of #R9, approximately 21.83 mg of powder was dosed to eachanimal, as an equivalent dose of 12 mg epinephrine.

The following pharmacokinetic parameters were calculated: peakconcentration in plasma (C_(max)), time to reach C._(max) (T_(max)), andarea under the concentration-time curve from time-zero to 24 hourspostdose (AUC_(0-24h)).

The pharmacokinetic behavior of epinephrine formulations was evaluated.At 5 minutes after a single-dose IM administration of epinephrine inrabbits, the mean plasma concentration of epinephrine was 0.988 ng/mL.In comparison, a sublingual administration of #R9 enabled a similarabsorption of epinephrine in the early phase. Specifically, #R9 showed amean epinephrine plasma concentration of 0.0.814 ng/mL at 5 minutespostdose. It was also noted that a plasma concentration of 0.713 ng/mLwas achieved at 5 minutes after a sublingual administration of #R6. Inaddition, #R9 showed a geometric mean Cmax of 7.0 ng/mL and a geometricmean AUC0-24 h of 1050.1 ng*min/L.

TABLE 58 Epinephrine Formulations for Rabbit Dosing Formulation #R1 #R2#R3 #R4 #R5 Epinephrine base 0 0.006 3.025 3.243 3.243 DiluteHydrochloric Acid 0.3 0.5 33.27 36.2 36.2 0.5N Dehydrated Alcohol 40 40Menthol 1 1 Sucralose 0.5 0.5 0.5 0.5 Propylene Glycol 5 5 SodiumBisulfite 0.2 0.01 0.2 0.3 0.3 Edetate Disodium 0.05 0.05 0.05 0.05(EDTA) Water USP 98.45 98.584 62.455 13.707 13.707 Total 100 100 100 100100

-   Components: % w/w

TABLE 59 Additional Epinephrine Formulations for Rabbit DosingFormulation #R6 #R7 #R8 Epinephrine base 6.648 12.88 12.88 DiluteHydrochloric Acid 1.5N 24.6 Dilute Hydrochloric Acid 3N 24.2 24.2Dehydrated Alcohol 40 40 40 Menthol 0.5 0.5 0.5 Sucralose 0.5 0.5 0.5Propylene Glycol 5 5 5 Sodium Bisulfite 0.6 0.6 0.6 Edetate Disodium(EDTA) 0.1 0.1 0.1 Water USP 21.552 15.72 15.72 Caprylic acid 0.5 Capricacid 0.5 Total 100 100 100

-   Components: % w/w

TABLE 60 Plasma concentrations for epinephrine after administration torabbits under fasted conditions. Formulation #R1 #R2 #R3 #R4 #R5 Routeof administration SL IM SL SL SL Dose per animal (mg) 0 0.03 3 3 6Concentration @ 5 min (ng/mL) 0.020 0.99 0.28 0.19 0.11 Concentration @10 min (ng/mL) 0.011 0.83 0.24 0.32 0.35 Concentration @ 15 min (ng/mL)0.014 0.79 0.49 0.55 0.86 Concentration @ 30 min (ng/mL) 0.012 0.73 0.441.24 1.94 T_(max) (min) 300 15 240 90 90 C_(max) (ng/mL) 0.05 1.1 1.32.9 6.3 AUC_(0-24 h) (ng*min/mL) 6.7 96.7 217.0 537.1 956.8

-   Plasma concentration: mean-   T_(max): median value-   C_(max) and AUC_(0-24h): geometric mean-   IM denotes intramuscular, SL denotes sublingual

TABLE 61 Plasma concentrations for epinephrine after administration torabbits under fasted conditions. Formulation #R6 #R7 #R8 #R9 Route ofadministration SL SL SL SL Dose per animal (mg) 6 12 12 12 Concentration@ 5 min (ng/mL) 0.71 0.28 0.12 0.81 Concentration @ 10 min (ng/mL) 0.370.46 0.17 1.10 Concentration @ 15 min (ng/mL) 0.51 0.83 0.53 1.40Concentration @ 30 min (ng/mL) 0.93 2.75 3.34 3.57 T_(max) (min) 120 120180 65 C_(max) (ng/mL) 3.1 6.0 14.3 7.0 AUC_(0-24 h) (ng*min/mL) 482.2867.0 2145.1 1050.1

-   Plasma concentration: mean-   T_(max): median value-   C_(max) and AUC_(0-24h): geometric mean

Example 8 Intranasal Administration of Epinephrine Spray Formulations

-   Methods

TABLE 62 Clinical Formulations Formulation #C1 #C2 Epinephrine Base2.962 3.178 Hydrochloric Acid 0.5N 32.93 35.471 Edetate DisodiumDihydrate 0.05 0.05 Sodium Bisulfite 0.15 0.15 Benzalkonium Chloride0.01 0.01 Dehydrated alcohol — 40 Sodium Chloride 0.6 — Water 63.29816.141

-   Components: % w/w

Protocol design was a Phase I, proof-of-concept, single-dose open-label,5-treatment, crossover study to assess the bioavailability of intranasalformulations in adults with seasonal allergies. The study assessed thebioavailability of a single dose 3 milligrams and 6 milligrams dose ofepinephrine in a formulation of the present invention to a single 0.3milligram intramuscular dose of epinephrine. 50 subjects were randomlyassigned to one of five groups including 3 milligram intranasal dose ofan aqueous formulation of the present invention, 3 milligram intranasaldose of a hydro-alcoholic formulation of the present invention, 6milligram intranasal dose of an aqueous formulation of the presentinvention, 6 milligram intranasal dose of a hydro-alcoholic formulationof the present invention and a 0.3 milligram intramuscular doseadministered over 4 periods with periods 1 and 2 administered in theabsence of allergen and periods 3 and 4 in the presence of an allergenthat caused seasonal allergies in the subject. Plasma concentrationswere taken at −60, −30, 0, 1, 3, 5, 10, 15, 20, 30, 40, 50, 60, 75, 90,120, 180, 240 and 360 minutes post-dose.

-   Results

TABLE 63 Pharmacokinetic profile prior to allergen exposure FormulationT_(max) (Mean) C_(max) (pg/mL) AUC_(last) (h*pg/mL) AUC_(inf) (h*pg/mL)Aqueous 0.376 (0.05-1.25) Mean 256 (23.4-1260) Mean 231 (31.4-958) Mean377 (37.9-1860) GeoMean 149 GeoMean 153 GeoMean 206 Hydro- 0.41(0.05-2.0) Mean 419 (77.6-1110) Mean 596 (30.7-3520) Mean 727(31.2-4150) alcoholic GeoMean 314 GeoMean 317 GeoMean 385 Epipen ® 0.281(0.05-0.833) Mean 511 (148-1160) Mean 307 (89.1-698) Mean 329 (91.4-749)GeoMean 429 GeoMean 255 GeoMean 273

TABLE 64 Pharmacokinetic profile after allergen exposure FormulationT_(max) (Mean) C_(max) (pg/mL) AUC_(last) (h*pg/mL) AUC_(inf) (h*pg/mL)Aqueous 0.13 (0.017-0.667) Mean 418(78.5-1900). Mean 231 (76.1-573).Mean 273 (94.9-620). GeoMean 268 GeoMean 197 GeoMean 237 Hydro- 0.12(0.017-0.667) Mean 639(60.6-3150). Mean 429 (51.8-963). Mean 497(52-1100). alcoholic GeoMean 447 GeoMean — GeoMean 376 Epipen ® 0.225(0.05-0.667) Mean 649(201-1750). Mean 317(125-557). Mean 362 (166-706).GeoMean 517 GeoMean 286 GeoMean 326

TABLE 65 Early Epinephrine plasma concentrations Time (Minutes) Mean(Min-Max) pg/ml Before Allergen Exposure Aqueous 1 47.8 (0-264) 3 154(0-749) 5 171 (9.17-844) 10 198 (9.37-1260) Hydro-alcoholic 1 84 (0-353)3 244 (6.73-933) 5 250 (2.13-1030) 10 200 (34.5-718) After AllergenExposure Aqueous 1 174 (1.77-1390) 3 353 (28.2-1900) 5 288 (31.3-1040)10 183 (36.2-461) Hydro-alcoholic 1 290 (10.5-1300) 3 581 (42.3-3150) 5398 (43.5-1340) 10 257 (20.6-692)

As seen in Tables 63-65 and FIGS. 1-3, subjects administered 6milligrams of epinephrine in a hydroalcoholic formulation of the presentinvention in the presence of an allergen had a higher C_(max) than allother cohorts. Further, as seen in FIGS. 1-3, subjects administered 0.3milligrams of epinephrine as an intramuscular injection in absence of anallergen had a higher C_(max) than all other cohorts in the absence ofan allergen. Among subjects receiving either the aqueous or thehydroalcoholic formulations the subjects receiving the hydroalcoholicformulations had a higher Cmax across the entire sampling time thanthose receiving the aqueous formulation both in the absence and presenceof an allergen. Epinephrine plasma concentrations were greater than 100pg/mL up to 30 min post dose for all formulations. Subjects administeredthe hydroalcoholic formulation had higher exposure in the entiresampling times for up to 6 hours compared to the aqueous formulation.

In conclusion, the bioavailability of intranasal formulations of thepresent invention is as good or better than that of the intramuscularinjection both in subject that are and are not experiencing seasonalallergies.

What we claim is:
 1. A method of treating anaphylaxis comprisingadministering via an assembled device an epinephrine formulationcomprising from about 0.1% w/w to about 15% w/w epinephrine or a saltthereof and from about 1% to about 80% w/w water, wherein theformulation has a pH from about 2 to about 5.5 and wherein w/w denotesweight by weight of the formulation.
 2. The method of claim 1 whereinthe assembled device comprises a reservoir, a plunger, a cannula, aspray pin, a reservoir holder and an actuator.
 3. The method of claim 1,wherein the assembled device comprises a reservoir, a piston and a swirlchamber.
 4. The method of claim 1, wherein the assembled device deliversone or more doses of the epinephrine formulation.
 5. The method of claim4, wherein assembled device is a unit-dose device that delivers one doseof the epinephrine formulation upon a single actuation and comprises asingle reservoir containing not more than 250 μL of the epinephrineformulation.
 6. The method of claim 5, wherein the single reservoircontains about 237 μL of the epinephrine formulation.
 7. The method ofclaim 6, wherein the assembled device delivers about 200 μL of thepharmaceutical formulation upon the single actuation.
 8. The method ofclaim 4, wherein the assembled device is a unit-dose device thatdelivers one dose of the epinephrine formulation upon a single actuationand comprises a single reservoir containing not more than 140 μL of theepinephrine formulation.
 9. The method of claim 8, wherein the singlereservoir contains about 127 μL of the epinephrine formulation.
 10. Themethod of claim 9, wherein the assembled device delivers about 100 μL ofthe pharmaceutical formulation upon the single actuation.
 11. The methodof claim 4, wherein the assembled device is a bi-dose device thatdelivers two doses of the epinephrine formulation upon two actuationsand delivers about 100 μL of the epinephrine formulation per actuation.12. The method of claim 4, wherein the device is a multi-dose devicethat delivers multiple doses of the epinephrine formulation uponmultiple actuations and delivers about 100 μL of the pharmaceuticalsolution per actuation.